Table 2.
Events, event rates and hazard ratios for baseline and time‐updated potassium levels for the various outcomes
| K+, mmol/L | Events, n (%) | Inc. rate, per 100 py | Baseline model | P‐value | Time‐updated model | P‐value | K+ by study drug interaction P‐value |
|---|---|---|---|---|---|---|---|
| Primary outcome | |||||||
| ≤3.5 | 70 (42.7) | 24.8 | 1.86 (1.46–2.37) | <0.001 | 1.91 (1.41–2.61) | <0.001 | 0.20 |
| 3.6–4.0 | 303 (28.3) | 14.1 | 1.25 (1.10–1.42) | 0.001 | 1.25 (1.06–1.47) | 0.009 | |
| 4.1–4.9 | 1277 (22.7) | 11 | Referent | – | Referent | – | |
| 5.0–5.4 | 292 (25.0) | 12.3 | 1.08 (0.95–1.23) | 0.25 | 1.08 (0.92–1.27) | 0.35 | |
| ≥5.5 | 47 (23.9) | 12.7 | 1.11 (0.83–1.48) | 0.50 | 1.38 (1.06–1.78) | 0.015 | |
| HF hospitalization | |||||||
| ≤3.5 | 40 (24.4) | 14.2 | 1.79 (1.29–2.47) | <0.001 | 2.01 (1.14–3.55) | 0.016 | 0.55 |
| 3.6–4.0 | 192 (18.0) | 8.9 | 1.39 (1.18–1.63) | <0.001 | 1.32 (9.98–1.77) | 0.063 | |
| 4.1–4.9 | 741 (13.2) | 6.4 | Referent | – | Referent | – | |
| 5.0–5.4 | 173 (14.8) | 7.3 | 1.08 (0.92–1.28) | 0.34 | 1.35 (1.03–1.77) | 0.028 | |
| ≥5.5 | 21 (10.7) | 5.7 | 0.85 (0.55–1.31) | 0.45 | 1.02 (0.50–1.08) | 0.95 | |
| CV death | |||||||
| ≤3.5 | 52 (31.7) | 16.1 | 2.25 (1.69–2.99) | <0.001 | 2.40 (1.84–3.14) | <0.001 | 0.45 |
| 3.6–4.0 | 177 (16.6) | 7.4 | 1.14 (0.97–1.35) | 0.11 | 1.27 (1.07–1.49) | 0.005 | |
| 4.1–4.9 | 778 (13.8) | 6.2 | Referent | – | Referent | – | |
| 5.0–5.4 | 186 (15.9) | 7.3 | 1.13 (0.97–1.34) | 0.11 | 1.19 (1.02–1.40) | 0.029 | |
| ≥5.5 | 37 (18.8) | 9.6 | 1.48 (1.06–2.06) | 0.021 | 1.42 (1.10–1.83) | 0.007 | |
| All‐cause death | |||||||
| ≤3.5 | 57 (34.8) | 17.6 | 2.00 (1.51–2.62) | <0.001 | 2.31 (1.80–2.96) | <0.001 | 0.41 |
| 3.6–4.0 | 215 (20.1) | 9 | 1.14 (0.98–1.33) | 0.084 | 1.26 (1.09–1.47) | 0.002 | |
| 4.1–4.9 | 963 (17.1) | 7.7 | Referent | – | Referent | – | |
| 5.0–5.4 | 235 (20.1) | 9.2 | 1.15 (1.00–1.33) | 0.052 | 1.26 (1.09–1.44) | 0.001 | |
| ≥5.5 | 47 (23.9) | 12.2 | 1.51 (1.12–2.02) | 0.006 | 1.37 (1.09–1.73) | 0.007 | |
| SCD or RCA | |||||||
| ≤3.5 | 21 (12.8) | 6.5 | 1.73 (1.11–2.70) | 0.015 | 2.45 (1.70–3.54) | <0.001 | 0.064 |
| 3.6–4.0 | 75 (7.0) | 3.1 | 0.90 (0.70–1.15) | 0.39 | 1.20 (0.95–1.52) | 0.13 | |
| 4.1–4.9 | 399 (7.1) | 3.2 | Referent | – | Referent | – | |
| 5.0–5.4 | 82 (7.0) | 3.2 | 1.03 (0.81–1.31) | 0.81 | 1.41 (1.13–1.75) | 0.002 | |
| ≥5.5 | 20 (10.2) | 5.3 | 1.65 (1.05–2.59) | 0.03 | 1.01 (0.64–1.59) | 0.97 | |
| Pump failure death | |||||||
| ≤3.5 | 15 (9.2) | 4.6 | 2.75 (1.61–4.70) | <0.001 | 3.43 (2.15–5.48) | <0.001 | 0.26 |
| 3.6–4.0 | 56 (5.2) | 2.3 | 1.54 (1.13–2.08) | 0.006 | 1.33 (0.96–1.85) | 0.087 | |
| 4.1–4.9 | 194 (3.5) | 1.6 | Referent | – | Referent | – | |
| 5.0–5.4 | 51 (4.4) | 2.0 | 1.18 (0.87–1.61) | 0.29 | 1.22 (0.91–1.65) | 0.19 | |
| ≥5.5 | 10 (5.1) | 2.6 | 1.54 (0.81–2.92) | 0.18 | 1.49 (0.93–1.37) | 0.095 | |
| Non‐CV death | |||||||
| ≤3.5 | 5 (3.1) | 1.5 | 0.83 (0.30–2.24) | 0.71 | 1.86 (0.95–3.66) | 0.072 | 0.46 |
| 3.6–4.0 | 38 (3.6) | 1.6 | 1.15 (0.80–1.64) | 0.45 | 1.24 (0.87–1.77) | 0.23 | |
| 4.1–4.9 | 185 (3.3) | 1.5 | Referent | – | Referent | – | |
| 5.0–5.4 | 49 (4.2) | 1.9 | 1.22 (0.88–1.67) | 0.23 | 1.54 (1.15–2.08) | 0.004 | |
| ≥5.5 | 10 (5.1) | 2.6 | 1.66 (0.87–3.15) | 0.12 | 1.17 (0.66–2.07) | 0.59 |
All models are adjusted on age, sex, race, region, systolic blood pressure, heart rate, body mass index, estimated glomerular filtration rate, ischaemic cardiomyopathy, left ventricular ejection fraction, N‐terminal pro brain natriuretic peptide, New York Heart Association class, hypertension, diabetes, atrial fibrillation, prior HF hospitalization, prior myocardial infarction, prior stroke, use of diuretics, digoxin, beta‐blockers, MRAs, cardiac devices, and treatment group allocation (sacubitril–valsartan or enalapril).
CV, cardiovascular; HF, heart failure; MRA, mineralocorticoid receptor antagonist; RCA, resuscitated cardiac arrest; SCD, sudden cardiac death or pump failure death.
The K+ group by study drug interaction P‐value refers to the interaction between the time‐updated potassium levels and the study drug (sacubitril–valsartan or enalapril). The interaction between the time‐updated potassium levels and eGFR (≤60 vs. >60 mL/min/1.73 m2) was also tested and none was significant (interaction P ≥ 0.1 for all the studied outcomes).